TRANSCRIPTION FACTOR AP-2 REGULATES HUMAN APOLIPOPROTEIN-E GENE-EXPRESSION IN ASTROCYTOMA-CELLS

Apolipoprotein E (apoE), one of the major plasma lipoproteins, also is expressed in a variety of cell types, including the glial cells of th e nervous system, apoE is involved in processes of degeneration and re generation after nerve lesions as well as in the pathogenesis of Alzhe imer's disease (AD), Glial synthesis of apoE is activated in response to injury both in the peripheral and central nervous system. We now re port that the activity of one proximal apoE promoter in astrocytes is upregulated by cAMP and retinoic acid, which act synergistically. Sequ ence analysis of the apoE promoter indicated the presence of several A P-2 consensus sequences that could mediate the stimulatory effect of c AMP and retinoic acid, The possible functional role of AP-2 was examin ed by cotransfection of AP-2-deficient HepG2 cells with an apoE promot er construct and a human AP-2 expression construct, Cotransfection wit h AP-2 significantly elevated apoE promoter activity. DNase I footprin ting technique revealed the existence of two binding sites for recombi nant AP-2 in regions from -48 to -74 and from -107 to -135 of the apoE promoter, Mutations in these regions markedly impaired the trans-stim ulatory effect of AP-2. These results indicate the existence of functi onal AP-2 sites in the promoter region of apoE that could contribute t o the complex regulation of this gene in developmental, degenerative, and regenerative processes of the nervous system.